EP0477885B1 - Dérivées d'hormone parathyroid - Google Patents

Dérivées d'hormone parathyroid Download PDF

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Publication number
EP0477885B1
EP0477885B1 EP91116303A EP91116303A EP0477885B1 EP 0477885 B1 EP0477885 B1 EP 0477885B1 EP 91116303 A EP91116303 A EP 91116303A EP 91116303 A EP91116303 A EP 91116303A EP 0477885 B1 EP0477885 B1 EP 0477885B1
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Prior art keywords
hpth
derivative
lys
amino acid
leu
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EP91116303A
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German (de)
English (en)
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EP0477885A3 (en
EP0477885A2 (fr
Inventor
Shizue Nakagawa
Tsunehiko Fukuda
Masahiro Kawase
Iwao Yamazaki
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel parathyroid hormone peptide derivatives useful in hormone therapy.
  • Parathyroid hormone is synthesized in the parathyroid, and plays an important role in controlling blood calcium concentrations or phosphoric acid ion concentrations by acting on the bone, the kidney and the intestine which are its target organs.
  • PTH is a peptide hormone consisting of 84 amino acids, and the biological action thereof can be reproduced by a peptide fragment of an N-terminal (1 through 34 amino acid) portion, G. W. Tregear et al., Endocrinology 93 , 1349-1353 (1973).
  • the amino acid sequence of the peptide fragment of the N-terminal (1 through 34 amino acid) portion of this human type PTH (this peptide fragment is hereinafter abbreviated as human PTH(1-34) or hPTH(1-34)) is as follows:
  • the inventors substituted one or more amino acid residue of human PTH(1-34) by chemical synthesis.
  • the substitutions effect the resulting molecule's resistance to various proteases, its two-dimensional structure as well as its reaction in hydrophilic/hydrophobic or ionic media.
  • a molecule which is an object of the present invention is synthesized.
  • clinically 5 effective PTH analogues have been synthesized in accordance with the present invention.
  • the present invention provides:
  • Peptide synthesis in the present invention can be carried out by the use of an automatic peptide synthesizer.
  • the method of R. B. Merrifield Advances in Enzymology 32 , 221-296 (1969) applies correspondingly to a basic synthesis course.
  • the amino acid of the carboxyl terminus is covalently bound to a resin carrier, and elimination of a protective group of an ⁇ -amino group and condensation of a protected amino acid are repeated in turn to extend a peptide chain to the amino terminus, thereby obtaining a protected peptide resin having a desired amino acid sequence.
  • This method is based on the above-described principle.
  • the resulting crude peptide can be purified by known means for purifying peptides or proteins.
  • known means for purifying peptides or proteins include column chromatography under various principles such as gel filtration, ion exchange chromatography using a cation exchange resin or an anion exchange resin, hydrophobic chromatography and partition adsorption chromatography, and high performance liquid chromatography.
  • the peptides of the present invention can be obtained in various salt forms.
  • the salts include salts of inorganic acids, salts of organic acids such as formic acid, acetic acid, tartaric acid and citric acid, salts of inorganic bases such as sodium and ammonium, and salts of organic bases such as triethylamine, ethylamine and methylamine.
  • the human PTH(1-34) derivative peptides of the present invention can be used as therapeutic agents for osteoporosis, hypoparathyroidism and hypertension.
  • the forms thereof include injections, nasotracheal absorption agents, perrectum absorption agents, transvaginal absorption agents, percutaneous absorption agents and eye drops. In some cases, they are orally administered.
  • peptides When the peptides are used as such therapeutic agents, effective amounts thereof are used to treat mammals, especially humans. Although they are generally used within the range of 1 ng to 100 ⁇ g/kg of weight, precise amounts thereof may be determined by those skilled in the art.
  • the peptides When used as the therapeutic agents, they must be carefully purified so as to contain no bacteria and no pyrogens.
  • the peptides when used as the therapeutic agents for osteoporosis, can be administered parenterally in the form of the above-described injections, nasotracheal absorption agents, perrectum absorption agents, transvaginal absorption agents, percutaneous absorption agents or eye drops, solely or in combination with pharmaceutically acceptable carriers, excipients or diluents.
  • the peptides are given to adults in a dose of 50 ng/kg to 5 mg/kg for 1 to 3 days, and preferably in a dose of 1 to 500 ⁇ g/kg for 1 to 3 days.
  • the concentration of the therapeutic agent is 10 to 100 ⁇ g/ml.
  • nucleotides and amino acids are indicated by abbreviations in this specification, the abbreviations adopted by the IUPAC-IUB Commission on Biochemical Nomenclature or those commonly used in the art are employed. For example, the following abbreviations are used.
  • amino acids are capable of existing as optical isomers, it is understood that the L-forms are represented unless otherwise specified.
  • the resistance to various proteases is increased and the persistence of the activity in blood is obtained.
  • This is achieved by, for example, substituting Aib for the 1st-position of PTH(1-34), and D- ⁇ -amino acid for the 12th-position of PTH(1-34).
  • the position around the 12-position Gly is considered to have the ⁇ -turn structure.
  • the substitution of a D-Ser for the Gly contributes to the stabilization of this structure, and the peptide chain is prevented from being digested by a protease at this position.
  • the affinity of the PTH derivatives for receptors is increased and high PTH activity is expressed by the substitution of amino acid residues at other positions.
  • the 11th position of PTH(1-34) is originally Leu.
  • the amino acid having an aromatic chain such as Phe is substituted for Leu.
  • Substitution of Gln or Leu for the 27th Lys; and substitution of 2-(1,3-dithiolane-2-yl)Trp for the 23rd Trp bring about high PTH activity expression.
  • the peptides were synthesized in accordance with a modified method of the solid phase peptide synthesis developed by R. B. Merrifield, R. B. Merrifield, Adv. Enzymol. 32, 221-296 (1969), and an automatic peptide synthesizer 430A (Applied Biosystems) was used. Protected peptide-resins were synthesized using protocols specified by Applied Biosystems.
  • Protected amino acid-p-oxymethylphenylacetoamidomethyl resins are used as starting materials when analogues having free carboxylic acids as carboxyl termini are desired, and 4-methylbenzhydryl resins are used as starting materials when analogues of carboxylamides are desired, and protected amino acids were condensed thereto successively.
  • a tertiary-butyloxycarbonyl (BOC) group was used. Side functional groups were protected in the following manner.
  • the protected peptide resin was taken out of the synthesizer and dried.
  • the peptide resin (1 g) was allowed to react with anhydrous hydrogen fluoride (8 ml) containing p-cresol (1 ml), 1,2-ethanedithiol (1 ml) and 2-mercaptopyridine (100 mg) at 0°C for 2 hours. After completion of reaction, hydrogen fluoride was removed by distillation and the residue was washed with diethyl ether to remove most of additives.
  • the peptide was extracted with 3% acetic acid (10 ml), and the resin was removed by filtration. The filtrate was purified by gel filtration using a Sephadex® G-25 column.
  • the conditions of gel filtration were as follows: column size: 2.8X60 cm; detecting wavelength: 230 or 280 nm; solvent: 3% acetic acid; flow rate: 40 ml/hour. Fractions containing the peptide were collected and then lyophilized.
  • the resulting powder sample was further purified by reversed phase high performance liquid chromatography [column: YMC-pack, A-324 ODS (10X250 mm); eluting solvent A: 0.1% trifluoroacetic acid-99.9% water; eluting solvent B: 0.1% trifluoroacetic acid-99.9% acetonitrile; linear gradient elution program: 0 minute (90% A + 10% B), 30 minutes (60% A + 40% B) (if necessary another elution program may be used); elution rate: 1.6 ml/minute; detecting wavelength: 230 or 280 nm].
  • the peptide was purified by reverse phase high performance liquid chromatography.
  • the conditions of the chromatography were as follows: Column, YMC-pack, A-324 ODS (10x250 mm); Eluent A, 0.1% trifluoroacetic acid - 99.9% water; Eluent B, 0.1% trifluoroacetic acid - 99.9% acetonitrile; Eluent concentration gradient program, 0 minute (70% A+ 30% B), 40 minutes (55% A + 45% B); flow rate: 1.6 ml/minute. Two large peaks (retention times 17.0 minutes and 18.2 minutes) were observed in the chromatography. The former peak (retention time 17.0 minutes) was recovered and changed to acetate by an ion-exchnage resin.
  • a compound (4mg) obtained from the peak at a retention time 18.2 minutes in the above high performance liquid chromatography was dissolved into 60mM sodium hydrogen carbonate pH8.0(2.6ml).
  • TPCK-trispin(160 ⁇ g) was added to the solution and reacted for 24 hours at 37°C, and then was inactivated by heating for 6 minutes at 100°C.
  • Aminopeptidese-M (0.5mg) was added to the resulting solution adjusted to pH7 and incubated at 37°C for 24 hours and then the enzyme(0.5 mg) was further added thereto. After an additional 48 hour period, the buffer (10 ml) and the enzyme (1 mg) were added thereto and reacted for 70 hours.
  • the biological activity of the peptide analogues was evaluated by a modified version of the method reported by Shigeno et al. in The Journal of Biological Chemistry 263, 18369-18377 (1988).
  • a culture solution (Hank's solution, containing 20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 0.1% bovine serum albumin and 0.5 mM isobutylmethyl-xanthine) containing 0.01, 0.1, 1, 10 or 100 nM analogue was added in an amount of 100 ⁇ l to a mouse cranial bone-derived osteoblast-like cell strain, MC3T3-EI cells, cultivated on a 96-well multiplate (Nunclon, Nunc), followed by reaction at room temperature for 30 minutes.
  • cyclic adenosine monophosphate (cAMP) produced by a PTH receptor was extracted from the cells.
  • the total cAMP in the culture solution and the cells was assayed using a commercial radioimmunoassay kit (cyclic AMP [ 125 I] kit "Du Pont-Daiichi", Daiichi Kagaku Yakuhin).
  • cyclic AMP [ 125 I] kit "Du Pont-Daiichi", Daiichi Kagaku Yakuhin An increase in cAMP production depending on the concentration of the human PTH (1-34) added as a standard was observed in each case.
  • the biological activity of the PTH (1-34) peptide analogues is shown in Table 2.

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  • Endocrinology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Claims (14)

  1. Dérivé d'hormone parathyroïdienne humaine (1-34) (hPTH (1-34)) ou sel de ce dernier, répondant à la formule :
    Figure 00270001
    dans laquelle R1 représente Ser ou Aib ; R3 représente Leu, Lys, Phe ou β-naphtyl-Ala ; R4 représente Gly ou D-Ser ; R9 représente Trp ou 2-(1,3-di-thiolan-2-yl)Trp ; R12 représente Lys, Gln ou Leu ; et R13 représente Phe ou Phe-NH2 ; à condition que :
    1) un peptide soit exclu, dans lequel R1 représente Ser, R3 représente Leu, R4 représente Gly, R7 représente Glu, R8 re-présente Val, R9 représente Trp et R12 représente Lys, et
    2) ledit peptide contienne de 3 à 5 résidus choisis parmi Ser pour R1, Leu pour R3, Gly pour R4, Trp pour R9, Lys pour R12 et Phe pour R13.
  2. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Aib1)hPTH (1-34).
  3. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Phe11)hPTH (1-34).
  4. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (D-Ser12)hPTH (1-34)NH2.
  5. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Lys11)hPTH (1-34)NH2.
  6. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Phe11)hPTH (1-34)NH2.
  7. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (3-(2-naphtyl)-Ala11)hPTH(1-34)NH2.
  8. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Gln27)hPTH (1-34).
  9. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Leu27)hPTH (1-34).
  10. Dérivé de hPTH (1-34) selon la revendication 1, qui est la (Lys11)hPTH (1-34).
  11. Dérivé de hPTH(1-34) qui est la (Arg19,21, 2-(1,3-dithiolan-2-yl)-Trp23)hPTH (1-34)NH2.
  12. Procédé pour produire un dérivé de hPTH (1-34) selon l'une quelconque des revendications 1 à 11, ou un sel de ce dernier, qui comprend (1) la liaison de l'acide aminé carboxy-terminal à un support résineux, (2) la répétition de l'élimination d'un groupe protecteur d'un groups α-amino, et de la condensation d'un acide aminé protégé pour allonger la chaíne peptidique en direction de l'extrémité amino, (3) l'obtention d'une résine peptidique protégée présentant une séquence voulue d'acides aminés, et (4) la séparation du peptide de la résine et l'élimination de tous les groupes protecteurs.
  13. Composition pharmaceutique pour la thérapie de l'ostéoporose, comprenant un dérivé de hPTH (1-34) ou un sel de ce dernier tel qui défini dans l'une quelconque des revendications 1 à 11.
  14. Utilisation d'un dérivé de hPTH (1-34) tel que défini dans l'une quelconque des revendications 1 à 11, ou d'un sel de ce dernier, pour la fabrication d'un médicament pour la thérapie de l'ostéoporose.
EP91116303A 1990-09-28 1991-09-25 Dérivées d'hormone parathyroid Expired - Lifetime EP0477885B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP25749090 1990-09-28
JP257490/90 1990-09-28
JP3227232A JPH0532696A (ja) 1990-09-28 1991-09-06 副甲状腺ホルモン誘導体
JP227232/91 1991-09-06

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EP0477885A2 EP0477885A2 (fr) 1992-04-01
EP0477885A3 EP0477885A3 (en) 1993-10-27
EP0477885B1 true EP0477885B1 (fr) 1999-01-20

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US (1) US5393869A (fr)
EP (1) EP0477885B1 (fr)
JP (1) JPH0532696A (fr)
AT (1) ATE175972T1 (fr)
CA (1) CA2052375C (fr)
DE (1) DE69130790T2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
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US7015195B2 (en) 2002-01-10 2006-03-21 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
US7795220B2 (en) 2003-03-19 2010-09-14 The General Hospital Corporation Conformationally constrained parathyroid hormones with alpha-helix stabilizers
US7910544B2 (en) 2003-07-17 2011-03-22 The General Hospital Corporation Conformationally constrained parthyroid hormone (PTH) analogs
US7985835B2 (en) 1998-10-22 2011-07-26 The General Hospital Corporation Bioactive peptides and peptide derivatives of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP)
US8143374B2 (en) 2006-08-04 2012-03-27 The General Hospital Corporation Polypeptide derivatives of parathyroid hormone (PTH)
US8568736B2 (en) 1999-09-29 2013-10-29 The General Hospital Corporation Polypeptide derivatives of parathyroid hormone (PTH)
US8568737B2 (en) 2007-08-01 2013-10-29 The General Hospital Corporation Screening methods using G-protein coupled receptors and related compositions

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DE3845000C2 (de) * 1987-07-10 1998-11-19 Novartis Ag Anwendung von Octreotid zur Behandlung von Brustkrebs
JPH05271279A (ja) * 1991-08-07 1993-10-19 Takeda Chem Ind Ltd ヒト副甲状腺ホルモンムテインおよびその製造法
US5317010A (en) * 1991-10-10 1994-05-31 Peter K. T. Pang Parathyroid hormone analogues substituted at AA 25, 26, 27, and use in osteoporosis treatment
DE4203040A1 (de) * 1992-02-04 1993-08-05 Boehringer Mannheim Gmbh Neue parathormonfragmente, deren herstellung und diese enthaltende arzneimittel
US5434246A (en) * 1992-03-19 1995-07-18 Takeda Chemical Industries, Ltd. Parathyroid hormone derivatives
US5382658A (en) * 1992-04-03 1995-01-17 Allelix Biopharmaceuticals Inc. Stability-enhanced variants of parathyroid hormone
EP0566135A1 (fr) * 1992-04-17 1993-10-20 Takeda Chemical Industries, Ltd. Composition transmucosale contenant un peptide et un dérivé de la cytidine
US5814603A (en) * 1992-06-12 1998-09-29 Affymax Technologies N.V. Compounds with PTH activity
CA2098639A1 (fr) * 1992-06-19 1993-12-20 K. Anne Kronis Variantes de l'hormone parathyroidienne osteostimulantes et non vasoactives
US5589452A (en) * 1992-07-14 1996-12-31 Syntex (U.S.A.) Inc. Analogs of parathyroid hormone and parathyroid hormone related peptide: synthesis and use for the treatment of osteoporosis
US5821225A (en) * 1992-07-14 1998-10-13 Syntex (U.S.A.) Inc. Method for the treatment of corticosteroid induced osteopenia comprising administration of modified PTH or PTHrp
US5977070A (en) * 1992-07-14 1999-11-02 Piazza; Christin Teresa Pharmaceutical compositions for the nasal delivery of compounds useful for the treatment of osteoporosis
AU672790B2 (en) * 1992-07-15 1996-10-17 Novartis Ag Variants of parathyroid hormone and its fragments
CN1070500C (zh) * 1993-07-13 2001-09-05 森德克斯(美国)股份有限公司 甲状旁腺激素类似物和甲状旁腺激素相关肽：合成和治疗骨质疏松症的用途
WO1995011697A1 (fr) * 1993-10-27 1995-05-04 Chugai Seiyaku Kabushiki Kaisha Accelerateur de guerison utilise en chondroplastie
CA2126299C (fr) * 1994-06-20 2000-12-12 Gordon E. Willick Analogues de l'hormone parathyroidienne utilises pour le traitement de l'osteoporose
US6110892A (en) 1994-06-20 2000-08-29 National Research Council Of Canada Parathyroid hormone analogues for the treatment of osteoporosis
US6117455A (en) * 1994-09-30 2000-09-12 Takeda Chemical Industries, Ltd. Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent
US5747456A (en) * 1994-12-19 1998-05-05 Beth Israel Deaconess Medical Center Continuous low-dose administration of parathyroid hormone or its agonist
DE69630918T2 (de) 1995-06-09 2004-10-28 Hisamitsu Pharmaceutical Co., Inc., Tosu Matrix für Iontophorese
CA2178894A1 (fr) * 1995-06-15 1996-12-16 Tsunehiko Fukuda Derives de la parathormone et leur utilisation
US6544949B1 (en) 1995-07-13 2003-04-08 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Analogs of parathyroid hormone
US5955574A (en) * 1995-07-13 1999-09-21 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. Analogs of parathyroid hormone
US7410948B2 (en) 1995-07-13 2008-08-12 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Analogs of parathyroid hormone
US5908400A (en) * 1996-06-20 1999-06-01 Hisamitsu Pharmaceutical Co., Inc. Device structure for iontophoresis
AU740610B2 (en) * 1996-12-27 2001-11-08 Chugai Seiyaku Kabushiki Kaisha Orthodontic remedies containing PTH
EP1721617A3 (fr) * 1997-07-22 2008-05-28 Chugai Seiyaku Kabushiki Kaisha Thérapeutiques dentaires comprenant de l'hormone parathyroide
US7531621B1 (en) * 1998-05-05 2009-05-12 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. PTH2 receptor selective compounds
EP1141237B1 (fr) 1998-12-31 2005-11-02 The General Hospital Corporation Recepteur pth et test de criblage l'utilisant
JP4723144B2 (ja) * 1999-09-29 2011-07-13 ザ ジェネラル ホスピタル コーポレイション 副甲状腺ホルモン（ｐｔｈ）のポリペプチド誘導体
US7022815B1 (en) 1999-09-29 2006-04-04 The General Hospital Corporation Polypeptide derivatives of parathyroid hormone (PTH)
US6756480B2 (en) * 2000-04-27 2004-06-29 Amgen Inc. Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein
KR100491737B1 (ko) * 2001-07-20 2005-05-27 주식회사 한국아이템개발 공기 정화 기능의 모기 퇴치기
CA2454275C (fr) * 2001-07-23 2012-10-23 The General Hospital Corporation Analogues d'hormone parathyroide (pth) a contrainte conformationnelle
KR100468907B1 (ko) * 2001-12-28 2005-02-02 김상길 벤토나이트 폐액 고화 처리용 고화제와 그 제조방법 및 이를 이용한 고형화 처리방법
AU2003239869A1 (en) * 2002-05-23 2003-12-12 Michael Holick Use of a parathyroid hormone peptide analogs for the treatment of vaginal atrophy
WO2004003145A2 (fr) * 2002-06-28 2004-01-08 Nastech Pharmaceutical Company Inc. Compositions et methodes permettant de moduler la physiologie de molecules d'adhesion jonctionnelle epitheliale en vue d'ameliorer l'administration de composes therapeutiques par voie muqueuse
BRPI0719885B8 (pt) * 2006-10-13 2021-05-25 Lilly Co Eli peptídeos peguilados como moduladores de receptores de pth, seus usos, e composição.
RU2604809C2 (ru) 2010-05-13 2016-12-10 Дзе Дженерал Хоспитал Корпорейшн Аналоги паратиреоидного гормона и их применение
US20140088014A1 (en) 2011-06-07 2014-03-27 Asahi Kasei Pharma Corporation Freeze-dried preparation containing high-purity pth and method for producing same
US20200354428A9 (en) 2013-06-23 2020-11-12 Wisconsin Alumni Research Foundation Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles

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US7985835B2 (en) 1998-10-22 2011-07-26 The General Hospital Corporation Bioactive peptides and peptide derivatives of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP)
US8568736B2 (en) 1999-09-29 2013-10-29 The General Hospital Corporation Polypeptide derivatives of parathyroid hormone (PTH)
US7015195B2 (en) 2002-01-10 2006-03-21 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
US7384912B2 (en) 2002-01-10 2008-06-10 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
US7795220B2 (en) 2003-03-19 2010-09-14 The General Hospital Corporation Conformationally constrained parathyroid hormones with alpha-helix stabilizers
US7910544B2 (en) 2003-07-17 2011-03-22 The General Hospital Corporation Conformationally constrained parthyroid hormone (PTH) analogs
US8143374B2 (en) 2006-08-04 2012-03-27 The General Hospital Corporation Polypeptide derivatives of parathyroid hormone (PTH)
US8568737B2 (en) 2007-08-01 2013-10-29 The General Hospital Corporation Screening methods using G-protein coupled receptors and related compositions

Also Published As

Publication number Publication date
JPH0532696A (ja) 1993-02-09
EP0477885A3 (en) 1993-10-27
CA2052375C (fr) 2001-10-30
DE69130790T2 (de) 1999-07-22
EP0477885A2 (fr) 1992-04-01
DE69130790D1 (de) 1999-03-04
CA2052375A1 (fr) 1992-03-29
ATE175972T1 (de) 1999-02-15
US5393869A (en) 1995-02-28

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